Project Summary Impairment in activities of daily living (ADL) is a hallmark of Alzheimer?s disease (AD) dementia and a major source of caregiver burden. Similar to cognitive and behavioral changes in AD, subtle difficulties in complex ADL may begin even before the stage of amnestic mild cognitive impairment (MCI). Preclinical AD consists of individuals with minimal or no symptoms but biomarker evidence of AD pathology. As secondary prevention trials in preclinical AD are being launched and the FDA is providing new guidance for early AD trial outcomes, it is imperative that we develop new ecologically valid instruments to detect subtle yet clinically meaningful alterations in complex ADL. Older individuals are increasingly required to interact via telephone and computer-based technology to perform essential ADL. The overall goal of this proposal is to optimize and validate a novel set of automated performance-based ADL instruments, the Harvard Automated Phone Task (APT) and computer- based Czaja Functional Assessment Battery (CFAB), which have been designed to tap the high level tasks that challenge seniors in daily life and to serve as ADL outcomes for preclinical and early prodromal AD clinical trials. For the first time, we have a chance to visualize regional tau deposition in vivo, using a new promising positron emission tomography (PET) tracer, T807, a.k.a. 18F-AV-1451. 1) To date, there have been no consistent associations between ADL performance and AD biomarkers in clinically normal (CN) elderly or early MCI alone. 2) We now have a unique opportunity to relate novel molecular imaging biomarkers of tau and amyloid to our novel ADL instruments. 3) There are no established instruments for detecting early ADL changes in CN individuals who may be in the preclinical stages of AD or in individuals with early prodromal AD. Here we seek to fill this gap in knowledge by further validating the Harvard APT and CFAB. The telephone is still the most prevalent technology mode of communication in the elderly, nearly all of whom in North America own a phone; about a third own a computer; more are starting to use smartphones; and most need to use an interactive voice response system (IVRS) to complete everyday activities. In the Harvard APT, subjects navigate an IVRS in order to refill a prescription (APT-Script), select a new physician (APT-PCP), and make a bank account transfer and payment (APT-Bank). In the CFAB, subjects refill a prescription (CFAB-Script) and perform automated teller machine (ATM) transactions (CFAB-ATM). These tasks simulate real-life activities commonly required of elderly. We will assess the Harvard APT and CFAB in 200 subjects (100 CN, 50 subjective cognitive decline (SCD), and 50 MCI), assess their relationship to cognitive function at baseline and over 3 years, assess their ability to track disease progression, and assess their relationship to AD imaging biomarkers. We will leverage a unique well-characterized sample from other funded studies to recruit the 100 CN subjects, who will already have imaging data and will only need to undergo the novel ADL tests. The 100 SCD and MCI subjects will be newly recruited and will undergo both clinical and imaging assessments.